This proposal describes a five-year training program for the development of an academic career in studying urologic diseases. The Principal Investigator has completed a PhD in molecular disease pathogenesis, postdoctoral training in diseases of the urinary tract and is presently in a period of transition as a junior faculty member at Northwestern University. This proposed program will lead to an understanding of the mechanisms of inflammation in the prostate gland. Dr. Anthony Schaeffer will mentor the Principal Investigator's scientific development. Dr. Schaeffer is a recognized leader in the fields of prostate inflammation and infectious diseases of the urinary tract. He is the Chair of Urology at Northwestern University and has trained numerous researchers and students. To further assist in providing guidance, an advisory committee of highly regarded medical scientists will be established to periodically review progress of the principal investigator. Research will focus on characterizing the role of toll-like receptors (TLR's) in prostate inflammatory responses and identifying the component pathways involved. Recent work by the principal investigator has shown that prostate epithelial cells express pattern recognition receptors (PRRs) like TLR4 that respond to inflammatory stimuli. The proposed studies will examine how TLR4 signaling occurs in prostate epithelial cells in response to lipopolysaccharide (LPS) from E. coli. In vitro culture models and a novel in vivo murine bacterial prostatitis model will be used. In culture, transcriptional factor activation will be studied following systematic siRNA silencing of the TLR4 signaling pathways. In vivo, chimeric mice will be used to determine the site of TLR4 functional immunity to E. coli. The Department of Urology at Northwestern University provides an ideal setting for training with close collaboration between clinical and basic scientists creating an environment conducive to the development of an academic career. PUBLIC HEALTH RELEVANCE: The proposed research will lead to a better understanding of the mechanisms of a number of urologic diseases including prostatitis and benign prostatic hyperplasia (BPH), conditions affecting millions of men.